As it is known, the term headache is currently taken to mean any form of more or less intense pain localised in the head. This pain may have various origins and in only about 10% of the cases it is caused by a specific organic illness, Under this profile it is possible to distinguish primitive or primary headaches, the cause of which is not accurately identifiable, and secondary headaches, which always constitute the symptom of another primary disorder, Examples of secondary headaches include sinusitis, headache due to cerebral hemorrhage, headache due to endocranial hypertension (in particular, caused by brain tumors), headache caused by infective meningitis and headache due to arterial hypertension. In all cases, the diagnosis calls for an accurate examination that not only takes the pain characteristics into account, but also the familiarity and relations with other disorders, causal factors and reactions to various pharmaceuticals, and in most cases requires a series of tests such as a blood test, X-rays of the cranium and cervical column, EEG and echography,
Once having excluded that the symptoms are linked to a different basic disorder, then it is likely that the disorder is one of the possible arms of primary headaches, often referred to as a “migraine”, which affect about 20-30% of the population (prevalently women). According to one of the current classifications, this may be of one of the following four forms: 1) classical migraine, i.e. with an aura; 2) common migraine, i.e. without an aura; 3) complicated migraine; 4) cluster headache.
Apart from the cluster headache, the aforesaid other forms of migraine generally consist of a pulsating periodic headache affecting one half of the cranium, and often associated with nausea and/or vomiting. The disorder generally starts in childhood, during adolescence and early adulthood and decreases in intensity and frequency over the years. In particular, a classical migraine starts with the so-called aura, consisting of protracted neurological symptoms for 30 minutes and includes photophobia, flashing scotoma (ie. bright flashing sensations before the eyes, with jagged edging similar to a wall), vertigo and tinnitus. With common migraines the headache arise with-out a prior aura, but often involves nausea or vomiting. Complicated migraines are instead characterised by headaches associated with particular neurological symptoms that may precede or accompany them. In particular, there may be paresthesia and hypoesthesia of the lips, face, hand and leg of al hemi-soma, sometimes associated with aphasic disorders, or one end of an arm or leg may become hyposthenic or plegic simulating an ictus. The sensitive disorders or feelings of weakness extend slowly from one side of the body to the other for a period a few minutes. Usually, after an attack, there in a complete return to normality, but there may also be permanent deficiencies among which hemianopsia, hemiplegia and hemianestesia. Cluster headache, also referred to as paroxysmal nocturnal headache, hemicranial neuralgia, histamine headache and Horton's syndrome, is four times more common in men than in women, and is characterised by a constant unilateral orbital pain generally beginning two or three hours after sleep onset. The pain is intense and steady but not pulsating, and involves lachrymation, nasal congestion, rhinorrhea and then myosis, reddening and oadema of the cheek that lasts for about 30 an hour. This form of headache tends to occur cyclically during the right for several weeks or months (hence the name “cluster”) and is then followed by a complete recovery for months or even years. Episodes of cluster headache of 2-3 week duration may arise several times in a lifetime.
The physiopathological mechanisms of the various forms of primary headache have been the subject of many studies and to date no pathogenetic theory that appears satisfactory to all researchers has been proposed. Many factors have been put forward as possible causes of a migraine attack, among which stress, physical strain, the weather, hormone fluctuations, bright lights and the intake of certain foods or beverages, such as those containing caffeine or alcohol. In any case, the migraine symptoms are always associated with variations in cerebral blood flow, presumably as a result of changes in blood vessel dimensions: normally, the prodromes are accompanied by arterial constriction and a reduction in cerebral blood flow, and are followed by blood vessel dilation corresponding to the actual headache onset. However, the factors which determine these changes in cerebral blood flow and the mechanisms through which such changes are linked to pain are controversial. One of the hypotheses claims that a migraine is due to a neurovascular disorder of the central nervous system (in particular, of the hypothalamus and brainstem) which involves alterations in vasomotor regulation, while another hypothesis interprets the disorder as a systemic metabolic imbalance with attacks caused by intravascular factors associated with serotonin (or 5-hydroxytriptamine, 5-HT) variations in the metabolism. It has been found, though, that migraines are accompanied by variations in platelet serotonin levels with a fall in these levels, during a migraine attack, due to the release —associated with increased urinary excretion —of its main metabolite, 5-hydroxyindolacetic acid.
According to some more recent observations, during a migraine attack there is an overflow of plasmatic proteins and the development of localised inflammation of intracranial blood vessels, together with the activation of trigeminal innervation of cerebral blood circulation. This phenomenon also sees the action of certain peptidic neurotransmitters which have a vasodilatory effect and are contained in the nerve fibres of the trigeminovascular system, in particular the CGRP (calcitonin gene-related peptide) and SP (substance P). These neurotransmitters appear to be particularly important in pain transmission and they are thought to be also involved in local tissue reactions of an inflammatory type. In particular, it has been demonstrated that substance P causes protein overflow and the typical inflammatory reaction triggered by the degranulation of mastocytes even in the brain dura mater, the connective tissue covering and protecting the brain matter, and which contains the cerebral blood vessels and their accompanying nerve fibres (Moskowitz M. A., Basic mechanisms in vascular headache, Neual. Clin. 8:801-415, 1990; Moskowitz M. A. and Outrer F. M., Sumatripan, a receptor-tareted treatment of migraine, Ann. Revs Med., 44:145-154, 1993; May A., Goadsby P. J., The Trigeminovascular System in Humans: Pathophysiological Implications for Primary Headache Syndromes of the Neural Influences on the Cerebral Circulation, J. Cereb. Blood Flow Metab., 19:115-117, 1999).
As well as the two aforesaid vasodilating neurotransmitters and serotonin, other chemical agents seem to be involved, depending on the cases, in causing headache pain, such as histamine (as the term histamine headaches attributed to the cluster headache implies), thromboxan A2, prostaglandins and quinines. Current migraine treatment partly takes these chemical agents into account with therapies that aim to neutralise their action. This is the case, for example, with anti-inflammatory drugs and analgesics currently used in particular cases of headache. Other currently used treatments are ergotamine and its derivatives; ergot alkaloids that appear to be mostly active against classical and common migraines, and only if taken early during an attack; metisergide, an antiserotoninegic drug (a strong antagonist of 5-HT1 recptors), especially useful as a preventive measure; and the selective agonists of the 5-HT1 receptors, above all, sumatryptan. The latter can trigger 5-HT1 serotonin receptors which mediate localised vasoconstriction at the carotid level, thereby reducing blood flow to the extra and intracranial tissues. Although effective in reducing the headache pain symptom, these products are not devoid of side-effects Moreover, to develop a quick response they need to be administered by subcutaneous injection.